As described by H Yu et al Nat. Rev. Cancer 2000, 9, 798-809, the signal transducer and activator of transcription (STAT) family proteins mediate a range of cellular responses to cytokines and growth factors. R Garcia et al Oncogene 2001, 20, 2499-2513 note the activation of STAT proteins is initiated by upstream growth factor receptors and cytoplasmic kinases such as Janus kinases (JAKs) and Src family kinases, thus culminating in the formation of activated STAT dimers by reciprocal phosphotyrosine-Src Homology 2 (SH2) domain interactions. T Bowman et al Oncogene, 2000, 19, 2474-2488 have reported the aberrant expression and constitutive activation of one of the STATs, STAT3, has been associated with tumorgenesis through upregulation of cell survival proteins and cell-cycle regulators, and G. Nu et al Oncogene 2002, 21, 2000-2008 reported enhanced angiogenesis of cells. In particular, L. Pedranzini et al J. Clin. Invest. 2004, 112, 629-622 and others have reported that STAT3 plays an important role in the development of skin cancer. Lanxi Song et al Oncogene 2003, 22, 4150-4165 discuss activation of STAT3 by receptor tyrosine kinases and cytokines and conclude that direct inhibition of STAT3 leads to apoptotic cell death in nonsmall cell lung carcinomas and that experiments with A549 and H1299 cells and suggest that STAT3 controls apomotic pathways in certain human lung cancer cells. C. Zhou at al Oncogene. 2014, 33, 851-861 note that STAT3 likely regulates a group of genes that control apoptotic pathways in a number of human cancer models, including breast (MCF7, MDA-MB-231, MDA-MB-453 and T47D cells), myeloma, colorectal (HCT116), prostate, pancreatic, ovarian (A2780 and SKOV3) and head and neck squamous cell carcinomas and various hematological malignancies. Blocking the STAT3 signaling pathway has been reported as inducing growth inhibition and apoptosis in human cervical cancer HeLa cells, human hepatocellular HepG2 cells, and skin squamous cell carcinoma A431 cells. (Oncol, Lett. 2013, 6, 1323-1328; Asian Pac. J. Cancer Prev. 2015, 16, 2813-2818).
The inhibition of STAT3 dimerization through occupation of the SH2 domain of STAT3 has been demonstrated by a number of small molecules. K. A. Siddiquee, et al ACS Chem. Biol. 2007, 2, 787-798; H. Li, et al J. Med. Chem. 2011, 54, 5592-5596 H. J. Chen, et al Eur. J. Med. Chem. 2013, 62, 498-507; and X. L. Zhang, et al Proc. Natl. Acad. Sci. USA 2012, 109, 9623-9628.
K. Siddiquee, et al Proc. Natl. Acad. Sci. USA 2007, 104, 7391-7396 have reported that S3I-201 (NSC 74859) induced the regression of human breast cancer xenografts in a nude mice model.
Sadler and coworkers developed organometallic ruthenium(II) anticancer complexes which exhibit in vitro and in vivo anticancer activities by inhibition of human glutathione-S-transferase π. (Y. Lin, et al J. Inorg. Biochem. 2009, 9, 798-809.) Recently, our group reported the first examples of rhodium(III) and iridium(III) complexes as inhibitors of the NEDD8-activating enzyme (NAE), tumor necrosis factor α (TNF-α), and the mammalian target or rapamycin (mTOR). (Angew. Chem. 2012, 124, 9144-9148; Angew. Chem. Int. Ed. 2012, 51, 9010-9014; Chem Plus Chem 2014, 79, 508-511)